MUTYH c.137A>C, p.Glu46Ala

Reasoning

PM2 at supporting strength is met. The supplied generic SVI threshold is <=0.0001. The governing data default to all-comers because no released MUTYH VCEP population rule specifies a non-cancer or exome-only source; the gnomAD v4.1 all-comers frequency is 4/1,614,016 (2.47829e-06), with grpmax FAF 7.9e-07, zero homozygotes, and a qualifying ancestry group of 1,179,902 alleles. The older non-cancer exome subset independently reports 1/236,860 (4.2219e-06), also <=0.0001. Thus the variant is present only at an extremely low frequency in controls, as permitted for a recessive disorder, and satisfies PM2 Supporting rather than strict complete absence.

Rule

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. ... PM2 (supporting): <= 0.0001 — SVI recommendation to downgrade PM2 to Supporting (ClinGen SVI 2020) (PMID:25741868)

Evidence considered

• Generic ACMG/AMP PM2 definition allows absence from controls or extremely low frequency if recessive; the supplied SVI recommendation sets PM2 Supporting at <=0.0001 (ClinGen SVI 2020, cited in the case threshold block as PMID:25741868).
• No released MUTYH VCEP criterion-specific rules are available, so the default all-comers gnomAD v2.1/v4.1 entries govern; the available non-cancer v2.1 exome result is also considered and is concordant.
• gnomAD v4.1 reports 4/1,614,016 alleles (AF 2.47829e-06), zero homozygotes, and grpmax FAF 7.9e-07; the European non-Finnish group has 4/1,179,902 alleles and therefore exceeds the 2,000-observed-allele minimum.
• gnomAD v2.1 non-cancer exomes report 1/236,860 alleles (AF 4.2219e-06) and zero homozygotes.
• The variant is not completely absent, so PM2 is applied at the supplied supporting strength for an autosomal-recessive disorder rather than as stronger evidence.

Sources

Reasoning

The variant is a missense substitution, so the governing generic rule selects the REVEL path only; SpliceAI and BayesDel are not used for BP4. REVEL is 0.023, which is <= 0.29 and therefore meets the generic BP4 supporting threshold (ClinGen SVI REVEL calibration, Pejaver et al. 2022, PMID:36413997).

Rule

BP4: Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)

Evidence considered

• NM_001048174.2:c.137A>C is a missense variant, NP_001041639.1:p.(Glu46Ala); under the generic rule, REVEL is the sole applicable computational path and SpliceAI is excluded.
• Local REVEL predictor lookup: score 0.023.
• Generic BP4 supporting calibration: <= 0.29, from the supplied ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet; PMID:36413997).

Sources

Reasoning

The variant lies at residue 46 of MUTYH. The authoritative vcep_materials.json domain_tables entry for MUTYH is absent, and the listed MUTYH specification has no released criterion defining a critical domain or hotspot route. The available Cancer Hotspots search found no statistically significant hotspot for MUTYH E46, so the generic PM1 requirement is not met on the supplied evidence.

Rule

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.

Evidence considered

• vcep_materials.json has domain_tables: {} for MUTYH, so there is no authoritative VCEP domain entry covering residue 46.
• The MUTYH InSiGHT specification is listed but has no released criteria and generic ACMG/AMP rules govern this interpretation.
• The Cancer Hotspots search for MUTYH E46 returned no result and states that the variant does not lie in a statistically significant hotspot.

Sources

Reasoning

The variant is a missense substitution, so the governing generic rule selects the REVEL path only; SpliceAI and BayesDel are not used for PP3. REVEL is 0.023, below the generic PP3 supporting threshold of >= 0.644 (ClinGen SVI REVEL calibration, Pejaver et al. 2022, PMID:36413997), so PP3 is not met.

Rule

PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... PP3 (supporting): >= 0.644 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)

Evidence considered

• NM_001048174.2:c.137A>C is a missense variant, NP_001041639.1:p.(Glu46Ala); under the generic rule, REVEL is the sole applicable computational path and SpliceAI is excluded.
• Local REVEL predictor lookup: score 0.023.
• Generic PP3 supporting calibration: >= 0.644, from the supplied ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet; PMID:36413997).

Sources

Reasoning

The governing ACMG/AMP definition is: "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation." The exact ClinVar record for NM_001048174.2:c.137A>C (p.Glu46Ala) has no expert-panel submission and contains three uncertain-significance laboratory submissions plus one likely-benign laboratory submission. No reviewed publication reports this exact variant as pathogenic. Therefore the required exact-variant reputable pathogenic report is absent, and PP5 is not met.

Rule

Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.

Evidence considered

• ClinVar exact-match record NM_001048174.2(MUTYH):c.137A>C (p.Glu46Ala) reports 0 expert-panel submissions, with three uncertain-significance submissions and one likely-benign single-laboratory submission.
• The literature_pass.json candidate papers and paper extracts do not report this exact variant as pathogenic; general MUTYH disease statements do not qualify as an exact-variant pathogenic report.
• Ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions were excluded from PP5.

Sources

Reasoning

BA1 is not met. Generic ACMG/AMP BA1 requires an allele frequency above 5%; the applicable generic stand-alone threshold supplied for this case is >=0.05. The highest qualifying filtering frequency is gnomAD v4.1 grpmax FAF 7.9e-07, based on a population with 1,179,902 observed alleles, far below 0.05. The gnomAD v4.1 all-comers frequency is 4/1,614,016 (2.47829e-06), and gnomAD v2.1 non-cancer exomes report 1/236,860 (4.2219e-06); none approaches the stand-alone threshold. The available ClinVar record is conflicting (three uncertain-significance submissions and one likely-benign submission), so there is no pathogenic consensus requiring the additional BA1 caution to override the frequency result.

Rule

Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. ... BA1 (stand-alone): >= 0.05 — ACMG/AMP 2015 stand-alone benign allele frequency (PMID:25741868)

Evidence considered

• Generic ACMG/AMP BA1 threshold supplied for this case: >=0.05, described as the stand-alone benign allele-frequency threshold under ACMG/AMP 2015 (PMID:25741868).
• gnomAD v4.1 all-comers reports 4/1,614,016 alleles (AF 2.47829e-06), zero homozygotes, and grpmax FAF 7.9e-07; the highest observed population is European non-Finnish at 4/1,179,902 alleles.
• The required filtering metric is used rather than the European non-Finnish popmax point estimate; the qualifying population has more than 2,000 observed alleles.
• gnomAD v2.1 non-cancer exomes report 1/236,860 alleles (AF 4.2219e-06) and zero homozygotes; no v2.1 FAF is reported.
• ClinVar variation 630651 has conflicting classifications: three clinical laboratories submitted uncertain significance and one submitted likely benign; there is no pathogenic consensus that would make a stand-alone BA1 call inappropriate on that basis.

Sources

Reasoning

BS1 is not met. Generic BS1 requires an allele frequency greater than expected for the disorder, with the supplied generic default threshold of >=0.01. The correct filtering metric is gnomAD v4.1 grpmax FAF, 7.9e-07, not the European non-Finnish popmax point estimate of 3.39011e-06; the FAF is based on a population with 1,179,902 observed alleles and is well below 0.01. gnomAD v2.1 non-cancer exomes show 1/236,860 alleles (4.2219e-06), also far below the default. No maximum-credible-frequency calculation is needed to resolve an elevated ancestry-specific signal because no qualifying frequency is near the threshold.

Rule

Allele frequency is greater than expected for the disorder. ... BS1 (strong): >= 0.01 — Generic SVI default; per-gene derivation preferred (Whiffin et al. 2017) (PMID:28518168)

Evidence considered

• Generic ACMG/AMP BS1 definition: the allele frequency must be greater than expected for the disorder; the supplied generic default threshold is >=0.01, with per-gene derivation preferred (Whiffin et al. 2017, PMID:28518168).
• gnomAD v4.1 reports grpmax FAF 7.9e-07 and total AF 2.47829e-06 from 4/1,614,016 alleles; the highest observed population point estimate is European non-Finnish 3.39011e-06 from 4/1,179,902 alleles.
• The grpmax FAF, rather than the popmax point estimate, is used for BS1, and the qualifying population has at least 2,000 observed alleles.
• gnomAD v2.1 non-cancer exomes report AF 4.2219e-06 from 1/236,860 alleles, with zero homozygotes.
• The observed frequencies are not elevated and do not require a disease-prevalence, penetrance, or allelic-heterogeneity correction to the generic default.

Sources

Reasoning

BS2 is not met. MUTYH-associated polyposis is autosomal recessive, so the generic BS2 path requires observation of the variant in a healthy adult as a homozygote, with full penetrance expected at an early age. gnomAD v2.1 non-cancer exomes and gnomAD v4.1 each report zero homozygotes; the records provide no qualifying healthy-adult homozygous observation. The absence of homozygotes does not support BS2, and no individual-level clinical observation supplies the criterion.

Rule

Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.

Evidence considered

• The governing MUTYH framework identifies familial adenomatous polyposis 2 as autosomal recessive, while no released VCEP criterion-specific rules are available; generic ACMG/AMP rules therefore govern.
• gnomAD v2.1 non-cancer exomes report 1/236,860 alleles and zero homozygotes.
• gnomAD v4.1 reports 4/1,614,016 alleles and zero homozygotes.
• No individual-level record documents a healthy adult who is homozygous for NM_001048174.2:c.137A>C.

Sources

Reasoning

The governing ACMG/AMP definition is: "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation." The exact ClinVar record contains one likely-benign ordinary laboratory submission, but no expert-panel submission; the overall record is conflicting and has a one-star criteria-provided status. Under the required generic PP5/BP6 restriction, an ordinary laboratory submission, aggregate ClinVar label, or non-expert assertion cannot trigger BP6. No reviewed publication provides an exact-variant reputable benign report. BP6 is therefore not met.

Rule

Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.

Evidence considered

• ClinVar exact-match record NM_001048174.2(MUTYH):c.137A>C (p.Glu46Ala) contains one likely-benign submission from Ambry Genetics, three uncertain-significance submissions, and 0 expert-panel submissions.
• The ClinVar record is conflicting and has criteria-provided, conflicting-classifications status rather than an exact-variant expert-panel benign classification.
• Ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions were excluded from BP6.

Sources

Reasoning

The variant is NP_001041639.1:p.(Glu46Ala), but the available case evidence does not establish a previously established pathogenic variant producing the same amino-acid change through another nucleotide change. ClinVar shows conflicting classifications for this exact variant, not a qualifying PS1 comparator, and no validated same-amino-acid pathogenic comparator is documented.

Rule

Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.

Evidence considered

• The case variant is NM_001048174.2:c.137A>C (NP_001041639.1:p.(Glu46Ala)).
• ClinVar variation 630651 reports conflicting classifications: three uncertain-significance submissions and one likely-benign submission, with no expert-panel submission.
• The PM5 candidate artifact reports zero same-residue candidates and explicitly does not establish a comparator; it cannot by itself support PS1.

Still missing

• A curated search of prior pathogenic variants with the same p.Glu46Ala amino-acid change is not available.

Sources

Reasoning

No case-specific evidence establishes that the variant is de novo in an affected proband, confirms both maternity and paternity, or documents absence of a family history. The available evidence contains no proband-level phenotype and no parental genotyping or parentage confirmation, so PS2 cannot be assessed.

Rule

De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.

Evidence considered

• The case-specific materials provide no individual-level proband, parental-testing, parentage-confirmation, or family-history observations for NM_001048174.2:c.137A>C (p.Glu46Ala).

Still missing

• Affected proband phenotype and disease diagnosis are not documented.
• Maternal and paternal variant testing results are not documented.
• Confirmation of both maternity and paternity is not documented.
• Family history is not documented.

Reasoning

The variant is NM_001048174.2:c.137A>C (NP_001041639.1:p.(Glu46Ala)) in MUTYH. The reviewed evidence contains no variant-specific in vitro or in vivo functional assay, assay controls, reproducibility information, clinical diagnostic validation, or quantitative result for this substitution. General MUTYH disease descriptions and computational predictions are not functional-study evidence. Therefore, the evidence is insufficient to assess PS3, and no PS3 strength is assigned.

Rule

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

Evidence considered

• The consolidated evidence identifies NM_001048174.2:c.137A>C as NP_001041639.1:p.(Glu46Ala) in MUTYH.
• The reviewed ACMG framework paper does not mention MUTYH or this exact variant and provides no variant-specific functional assay result.
• The reviewed MUTYH technical standards document discusses MUTYH-associated polyposis generally but reports no functional assay or variant-specific experimental result for c.137A>C (p.Glu46Ala).
• No validated assay controls, reproducibility data, clinical diagnostic laboratory validation, or quantitative functional measurement for this variant was available in the reviewed evidence.

Still missing

• A variant-specific functional study is needed, including appropriate wild-type and damaging controls, biological relevance to MUTYH function, reproducibility, and quantitative results.

Sources

Reasoning

The governing ACMG/AMP rule is: "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls." Note 1 requires: "Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0." No paper in the literature_pass packet's ai_classified_papers list was available (the list is empty), and the reviewed candidate papers either do not mention NM_001048174.2:c.137A>C / p.(Glu46Ala) or are general guidelines. The gnomAD records provide population-control allele counts (gnomAD v4.1: 4/1,614,016 total alleles; 4/1,179,902 European non-Finnish alleles) but no affected-case count or matched case-control study, so an OR and 95% CI cannot be computed. The required case-control comparison is therefore not assessable, rather than negative.

Rule

The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.

Evidence considered

• gnomAD v4.1 reports the exact variant at 4/1,614,016 total alleles (AF 2.47829e-06) and 4/1,179,902 European non-Finnish alleles (AF 3.39011e-06), which supplies population-control data only.
• The literature_pass.json ai_classified_papers list is empty; the reviewed candidate papers did not provide an exact-variant affected cohort, unaffected cohort, or case-control counts.
• No OR or 95% CI was computed because the affected-case numerator and denominator are absent.

Still missing

• Affected-case carrier count and denominator for NM_001048174.2:c.137A>C are unavailable.
• A matched-control count or matched-ancestry control frequency suitable for an OR and 95% CI is unavailable.

Sources

Reasoning

MUTYH-associated polyposis is an autosomal-recessive disorder, so PM3 would require this NM_001048174.2:c.137A>C (p.Glu46Ala) allele to be demonstrated in trans with a pathogenic or likely pathogenic allele in an affected individual. The available evidence contains no affected-proband observation with a second pathogenic MUTYH variant and no parent, offspring, or other validated phase testing establishing trans configuration. General disease references support recessive inheritance but do not report this variant or provide phase information; therefore PM3 cannot be assessed.

Rule

For recessive disorders, detected in trans with a pathogenic variant...Note: This requires testing of parents (or offspring) to determine phase.

Evidence considered

• The CSPEC record identifies familial adenomatous polyposis 2/MUTYH disease as autosomal recessive but provides no released criterion specification or case-specific phase data.
• Hegde et al. (PMID:24310308) states generally that MYH-associated polyposis is caused by MUTYH mutations and inherited autosomal recessively; it does not mention c.137A>C or provide phase data.
• Stoffel et al. (PMID:25452455) describes MUTYH-associated polyposis as autosomal recessive and discusses biallelic carriers; it does not mention c.137A>C or provide phase data.
• Kalia et al. (PMID:27854360) classifies MUTYH-associated polyposis as autosomal recessive and recommends analysis in individuals with biallelic mutations; it does not report this variant or phase.

Still missing

• Documented affected-proband or affected-family observation carrying NM_001048174.2:c.137A>C and a pathogenic MUTYH variant.
• Parent, offspring, or equivalent laboratory phasing establishing that the two variants are in trans.

Sources

Reasoning

The variant is a missense change at MUTYH residue 46, but the available evidence does not document a different missense variant at residue 46 that has been determined to be pathogenic. The collected PM5 artifact contains zero same-residue candidates and warns not to apply PM5 from that artifact alone.

Rule

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

Evidence considered

• The case variant is p.Glu46Ala at MUTYH residue 46.
• The PM5 candidate artifact reports zero same-residue candidates, zero expert-panel pathogenic/likely-pathogenic candidates, and zero non-expert majority pathogenic/likely-pathogenic candidates; it instructs review rather than applying PM5 automatically.
• ClinVar variation 630651 provides conflicting classifications for the case variant itself and does not document a qualifying pathogenic alternate missense change at residue 46.

Still missing

• A validated search of ClinVar and literature for pathogenic alternate missense substitutions at MUTYH residue 46 is not available.

Sources

Reasoning

No case-specific evidence documents an assumed de novo occurrence in an affected proband. There are no parental genotypes, parentage data, or proband-level clinical observations showing that the variant arose de novo without confirmed maternity and paternity, so PM6 cannot be assessed.

Rule

Assumed de novo, but without confirmation of paternity and maternity.

Evidence considered

• The case-specific materials provide no individual-level proband, parental-testing, or assumed-de-novo observations for NM_001048174.2:c.137A>C (p.Glu46Ala).

Still missing

• Affected proband phenotype and disease diagnosis are not documented.
• Parental variant testing results are not documented.
• The basis for assuming a de novo event is not documented.

Reasoning

No affected relatives, variant-positive relatives, variant-negative relatives, meioses, or family-level phenotype data are reported. Although MUTYH is recognized in the case context as associated with familial adenomatous polyposis 2, the required family co-segregation observations for this variant are absent, so PP1 cannot be assessed.

Rule

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.

Evidence considered

• The case-specific materials provide no family pedigree, affected-relative phenotype data, relative genotypes, or meiosis count for NM_001048174.2:c.137A>C (p.Glu46Ala).

Still missing

• Affected family members and their phenotypes are not documented.
• Variant genotypes for relatives are not documented.
• Informative meioses and the number of segregating individuals are not documented.

Reasoning

The available case evidence does not establish both PP2 requirements: a low rate of benign missense variation in MUTYH and missense variants as a common disease mechanism. The supplied data show only the frequency of this individual variant and general MUTYH loss-of-function context, which are insufficient for the gene-level PP2 determination.

Rule

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

Evidence considered

• The supplied gnomAD data report this variant's frequency only: AF 2.47829e-06 in gnomAD v4.1, not a gene-level benign-missense constraint metric.
• The available gene-context material supports MUTYH loss of function as a disease mechanism but does not establish that missense variants are a common disease mechanism.

Still missing

• A gene-level assessment of benign missense constraint for MUTYH is unavailable.
• A gene-level assessment showing missense variants are a common MUTYH disease mechanism is unavailable.

Reasoning

The governing ACMG/AMP definition is: "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology." The case materials identify the variant and gene but do not provide the patient's phenotype, family history, or a disease-specific clinical presentation. The available MUTYH literature is general gene/disease context and does not establish this patient's phenotype as highly specific for a single genetic etiology.

Rule

Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.

Evidence considered

• The case summary contains no patient phenotype or family-history data for this variant.
• General MUTYH-associated polyposis descriptions in the reviewed literature are not evidence of this patient's phenotype.

Still missing

• Patient phenotype and diagnostic findings are unavailable.
• Family history and assessment of phenotypic specificity are unavailable.

Sources

Reasoning

The variant is NM_001048174.2:c.137A>C (NP_001041639.1:p.(Glu46Ala)) in MUTYH. The reviewed evidence contains no variant-specific in vitro or in vivo functional assay demonstrating preserved protein function or normal splicing, and no assay controls, reproducibility information, clinical diagnostic validation, or quantitative result. General MUTYH disease descriptions and computational predictions cannot establish absence of a damaging effect under BS3. Therefore, the evidence is insufficient to assess BS3, and no BS3 strength is assigned.

Rule

Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.

Evidence considered

• The consolidated evidence identifies NM_001048174.2:c.137A>C as NP_001041639.1:p.(Glu46Ala) in MUTYH.
• The reviewed ACMG framework paper does not mention MUTYH or this exact variant and provides no variant-specific functional assay result.
• The reviewed MUTYH technical standards document discusses MUTYH-associated polyposis generally but reports no functional assay or variant-specific experimental result for c.137A>C (p.Glu46Ala).
• No validated assay controls, reproducibility data, clinical diagnostic laboratory validation, or quantitative functional measurement demonstrating preserved function or normal splicing was available in the reviewed evidence.

Still missing

• A variant-specific functional study is needed to demonstrate preserved protein function or normal splicing using appropriate controls, biologically relevant methods, reproducibility, and quantitative results.

Sources

Reasoning

No affected family members who lack the variant are identified, and no family-level phenotype or genotype data permit evaluation of non-segregation. The BS4 phenocopy caveat also cannot be evaluated because the relevant family and phenotype information is absent, so BS4 cannot be assessed.

Rule

Lack of segregation in affected members of a family.

Evidence considered

• The case-specific materials provide no affected-relative genotypes, family phenotypes, or non-segregation observations for NM_001048174.2:c.137A>C (p.Glu46Ala).

Still missing

• Affected relatives are not identified.
• Variant-negative testing results in affected relatives are not documented.
• Family phenotypes and possible phenocopies are not documented.

Reasoning

The available evidence does not establish that MUTYH disease is caused primarily by truncating variants. Although the supplied gene context supports loss of function as a disease mechanism, it does not provide the required variant-spectrum evidence that truncating variants are the primary disease-causing class.

Rule

Missense variant in a gene for which primarily truncating variants are known to cause disease.

Evidence considered

• The supplied gene context states that MUTYH loss of function is a supported germline disease mechanism, but it does not quantify the proportion or predominance of truncating pathogenic variants.
• The case evidence does not provide a validated gene-level comparison of truncating versus missense pathogenic variants.

Still missing

• A curated MUTYH pathogenic-variant spectrum demonstrating that disease is primarily caused by truncating variants is unavailable.

Reasoning

BP2 requires either a trans observation with a pathogenic variant in a fully penetrant dominant disorder or a cis observation with a pathogenic variant in any inheritance pattern. The available evidence provides no validated parent/offspring testing, haplotype data, affected-proband observation, or other phase result showing NM_001048174.2:c.137A>C (p.Glu46Ala) in cis or trans with a pathogenic variant. Therefore BP2 cannot be assessed.

Rule

BP2: Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.

Still missing

• Validated phase evidence showing c.137A>C in cis with a pathogenic variant or in trans in a fully penetrant dominant disorder.

Reasoning

The governing ACMG/AMP definition is: "Variant found in a case with an alternate molecular basis for disease." The case materials contain no documented alternate molecular diagnosis, second pathogenic variant, or other molecular basis in the patient. Therefore the criterion cannot be assessed from the available evidence; absence of such documentation is not evidence that BP5 is met or not met.

Rule

Variant found in a case with an alternate molecular basis for disease.

Evidence considered

• No alternate pathogenic variant, molecular diagnosis, or other alternate molecular basis is documented in the case materials.

Still missing

• Patient-level testing for an alternate molecular basis is unavailable.
• The patient's disease diagnosis and molecular findings beyond this variant are unavailable.