The LDLR NM_000527.5:c.621C>T (NP_000518.1:p.(Gly207=)) synonymous variant has previously been reported in somatic cancers (COSMIC; COSV52944419, n = 1 time). Based on available guidelines, this variant is considered to be Pathogenic.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A pathogenic classification under the recorded framework.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.LDLR encodes a cell-surface receptor that removes low-density lipoprotein (LDL) and cholesterol from the bloodstream into cells, helping regulate cholesterol levels and synthesis. Inherited defects in LDLR cause familial hypercholesterolemia, an autosomal dominant disorder characterized by abnormally high cholesterol. LDLR is not known to have a direct cancer association.
The recorded framework is ClinGen LDLR VCEP v1.2. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met, very strong: c.621C>T causes a stable mRNA with a demonstrated 75-bp in-frame deletion, removing 25 LDLR amino acids.
Met strong: PMID:18400033 reports 35 unrelated FH index cases, exceeding the VCEP threshold of ≥10, and grpmax FAF 6.8e-7 satisfies PM2.
Met at Moderate: gnomAD v4.1 group maximum FAF is 6.8e-7, below the VCEP PM2 PopMax MAF threshold of 0.0002.
Met supporting: the variant was identified in clinically diagnosed FH patients after known alternative molecular causes were excluded, and grpmax FAF 6.8e-7 satisfies PM2.
No benign criterion marked as applied in the recorded assessment.
Pathogenic: PVS1 (very strong), PS4 (strong), PM2 (moderate), and PP4 (supporting) satisfy ACMG/AMP 2015 Table 5.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 4 / 1,613,612 alleles. Recorded AF 2.47891e-06. Recorded homozygote count 0.
Absent from gnomAD v2.1.
Not available in gnomAD-Canada v1.0.
Recorded SpliceAI maximum delta score: 0.981. Refer to the recorded PP3/BP4 rationale for interpretation.
10 Pathogenic · 1 Likely pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has previously been reported in somatic cancers (COSMIC; COSV52944419, n = 1 times).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under ClinGen LDLR VCEP v1.2, with the data and sources behind each one.
28 criteria with recorded statuses: 4 met · 2 not met · 12 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
PS1, PM1, and PM5 are all not applicable under the LDLR VCEP Version 1.2 rules because the queried variant is synonymous rather than missense.
Within the requested phenotype/prevalence group, PS4 is met at Strong from 35 unrelated FH index cases in PMID:18400033 plus the required VCEP PM2 condition; PP4 is met at Supporting from the same clinically diagnosed FH cohort with known alternative molecular causes excluded.
PP5, BP5, and BP6 are not applicable because the LDLR FH VCEP explicitly excludes them or states that they are not for use.
The population evidence supports PM2 at Moderate strength; BA1 and BS1 are not met because the gnomAD v4.1 group maximum FAF is below both benign-frequency thresholds, while BS2 cannot be assessed without qualifying normolipidemic adult phenotype data.
No criteria match.
NM_000527.5:c.621C>T is a synonymous exon 4 variant on the VCEP preferred transcript, but PMID:18400033 directly demonstrated a cryptic 3′ splice-donor site and aberrant stable mRNA containing a 75-bp in-frame deletion, removing 25 amino acids from the LDLR protein. The VCEP establishes LDLR loss of function as a disease mechanism and directs PVS1 strength through its Figure 1 flow diagram; this experimentally demonstrated abnormal transcript is consistent with the full-strength PVS1 path. No VCEP-specific downgrade rule is supplied in the available criterion entry for this demonstrated splice-altering event.
See PVS1 flow diagram (Figure 1).
The VCEP Strong PS4 rule requires the variant in ≥10 unrelated FH cases with diagnosis met by validated clinical criteria and requires PM2. PMID:18400033 explicitly identifies LDLR c.621C>T/G186G in 35 unrelated index cases from a cohort of 1350 clinically diagnosed FH patients after exclusion of known functional LDLR, APOB, and PCSK9 variants. This exceeds the VCEP case threshold (35 ≥ 10). The variant also meets the VCEP PM2 caveat: gnomAD v4.1 reports grpmax FAF 6.8e-7, and the VCEP PM2 threshold is MAF ≤0.0002 (0.02%), so 0.00000068 ≤ 0.0002? yes. The literature-pass PS4 leads were checked: PMID:10735632 reports only 1–2 individuals for newly identified variants and does not independently meet PS4; PMID:18400033 provides the decisive case count. No control allele count or odds ratio is reported in the cited variant-specific extracts, so no case-control OR/95% CI was computed; the VCEP's rare-variant case-count path is met instead.
Variant is found in ≥10 unrelated FH cases (FH diagnosis met by validated clinical criteria). Caveat: variant must also meet PM2
PM2 is met at Moderate strength. The LDLR VCEP requires a PopMax MAF of at most 0.0002 (0.02%) in gnomAD, with consideration of known founder variants. In the default all-comers gnomAD v4.1 data, the group maximum FAF is 6.8e-7 and the highest observed population AF is 1.60031e-5 (1/62,488 alleles), both below 0.0002; no founder exception is documented in the available evidence. The VCEP does not specify a non-cancer or exome-only source, so the all-comers gnomAD v4.1 entry is used.
Variant has a PopMax MAF ≤0.0002 (0.02%) in gnomAD. Consider exceptions for known founder variants.
The VCEP PP4 Supporting rule applies to any LDLR variant identified in an FH patient diagnosed by validated clinical criteria after alternative causes of high cholesterol are excluded, with a PM2 caveat. PMID:18400033 identifies c.621C>T/G186G in clinically diagnosed FH patients and states that the study cohort excluded known functional LDLR, APOB, and PCSK9 variants. The variant also meets PM2: grpmax FAF is 6.8e-7 versus the VCEP PM2 threshold MAF ≤0.0002 (0.02%), so 0.00000068 ≤ 0.0002? yes. The available report does not provide an individual Dutch Lipid Clinic Network score, Simon Broome category, or MEDPED result, but it explicitly describes a clinically diagnosed FH cohort with alternative known molecular causes excluded; this is treated as satisfying the VCEP's stated FH-patient path.
Any LDLR variant identified in an FH patient [diagnosis based on validated clinical criteria, e.g. Dutch Lipid Clinic Network (≥6), Simon Broome possible/definite), MEDPED], after alternative causes of high cholesterol are excluded. Caveat: variant must also meet PM2.
BA1 is not met. The LDLR VCEP requires a PopMax FAF of at least 0.005 (0.5%) in gnomAD. In the default all-comers gnomAD v4.1 data, the variant's group maximum FAF is 6.8e-7, and its total allele frequency is 2.47891e-6 (4/1,613,612 alleles; 0 homozygotes), all far below the BA1 threshold. The VCEP rule does not specify a non-cancer or exome-only source, so the all-comers gnomAD v4.1 entry is used.
Variant has a PopMax FAF ≥0.005 (0.5%) in gnomAD.
BS1 is not met. The LDLR VCEP requires a PopMax FAF of at least 0.002 (0.2%) in gnomAD. In the default all-comers gnomAD v4.1 data, the variant's group maximum FAF is 6.8e-7, below the BS1 threshold; the total AF is 2.47891e-6 with 4 alternate alleles among 1,613,612 alleles and no homozygotes. The VCEP rule does not specify a non-cancer or exome-only source, so the all-comers gnomAD v4.1 entry is used.
Variant has a PopMax FAF ≥0.002 (0.2%) in gnomAD.
The VCEP requires the variant to be de novo in a patient with the disease and no family history. The available evidence does not document confirmed maternity and paternity, parental genotypes, or absence of family history for this patient; therefore PS2 cannot be evaluated.
Variant is de novo in a patient with the disease and no family history. Follow SVI guidance for de novo occurrences: https://clinicalgenome.org/working-groups/sequence-variant-interpretation/
The VCEP allows PS3 Supporting for an RNA study from heterozygous or homozygous patient cells when an aberrant transcript is confirmed by sequencing, without transcript quantification. PMID:18400033 directly studied NM_000527.5:c.621C>T (G186G/Gly207Gly) in patient blood RNA and showed an aberrantly spliced, stable mRNA with an in-frame deletion of 75 nucleotides, but the reported method was cDNA PCR followed by agarose-gel electrophoresis and the paper does not document confirmation of the aberrant transcript by sequencing. The study therefore does not establish the VCEP's required Level 3 PS3 condition; the VCEP Level 2 and Level 1 conditions are also not evaluable because the study does not provide the required transcript quantification or whole-cycle heterologous-cell assay results. PMID:31578082 evaluated other LDLR variants and does not mention or test c.621C>T, so it cannot supply variant-specific functional evidence.
Variant meets Level 3 pathogenic functional study criteria. See Table 3. (1) Study of LDLR cycle (whole or part) in heterozygous patient cells, with assay results of <85% of wild-type activity in either LDLR expression/biosynthesis, LDL binding OR internalization. (2) Luciferase studies with transcription levels of <50% compared to wild-type (applicable to 5’UTR/promoter variants). (3) Minigene splicing assays with <10% wild-type transcript present where anaberrant transcript from the candidate variant is confirmed by sequencing. (4) High-throughput assays, which include alternative microscopy assays (e.g.,Thormaehlen et al., 2015), Multiplex Assays of Variant Effect (MAVE) (e.g.,Weile & Roth, 2018) and deep mutational scanning assays, can be considered here, only if assay has been validated with a minimum of four pathogenic and four benign variant controls in LDLR. Note: % activity thresholds will be defined by the FH VCEP as more data becomes available. (5) RNA studies, using RNA extracted from heterozygous or homozygous patient cells, with aberrant transcript confirmed by sequencing (but without transcript quantification).
The VCEP permits PM3 at Moderate strength only when the candidate LDLR variant is observed in an individual with a homozygous FH phenotype and there is exactly one other pathogenic or likely pathogenic variant in LDLR in trans, APOB, or PCSK9; the candidate must also meet PM2. The case evidence documents that c.621C>T was reported in two homozygous FH individuals, but it does not identify a second pathogenic or likely pathogenic variant or establish its phase in either individual. The variant's gnomAD v4.1 group maximum FAF is 6.8e-7, below the VCEP PM2 threshold of 0.0002, but the required allelic partner and trans phase are unavailable, so PM3 cannot be evaluated.
This criterion can be used for a candidate LDLR variant observed in an individual with a homozygous FH phenotype when there is only one other pathogenic or likely pathogenic variant in LDLR (in trans), APOB or PCSK9. Caveat: variant must also meet PM2.
The VCEP defines PM6 as the moderate-strength pathway for PS2 and provides no separate PM6 evidence rule. Because the required de novo evidence for PS2 is not documented, PM6 cannot be evaluated.
See PS2 above.
The VCEP requires segregation with phenotype in 2-3 informative meioses for supporting, 4-5 for moderate, or at least 6 for strong, with the specified affected relatives and LDL-C thresholds. PMID:18400033 reports 35 unrelated index cases and 62 first-degree relatives, but the available extraction does not provide family-level genotypes, informative-meiosis counts, or LDL-C values showing which relatives met the required threshold. The criterion therefore cannot be assigned.
Variant segregates with phenotype in ≥6 informative meioses in ≥1 family. Must include ≥2 affected relatives (LDL-C >75th centile) with the variant. ... Variant segregates with phenotype in 4-5 informative meioses in ≥1 family. Must include ≥2 affected relatives (LDL-C >75th centile) with the variant. ... Variant segregates with phenotype in 2-3 informative meioses in ≥1 family. Must include ≥1 affected relative (LDL-C >75th centile) with the variant.
The VCEP limits PP3 to REVEL >=0.75 for missense variants or predicted splice impact using MaxEntScan. This variant is synonymous, so the missense path does not apply. The available computational result is SpliceAI max delta 0.981, and PMID:18400033 reports a splice prediction with SPLICESITEFINDER plus aberrant splicing; neither is MaxEntScan. Because the governing rule names MaxEntScan and no MaxEntScan result or the VCEP's Figure 2 threshold application is available, PP3 cannot be assessed without substituting an ungoverned predictor.
REVEL score ≥0.75 (missense variants), or predicted impact to splicing using MaxEntScan (see Fig. 2 for suggested thresholds).
BS2 cannot be assessed. The VCEP requires identification of the variant in at least 3 heterozygous or at least 1 homozygous well-phenotyped, untreated, normolipidemic, unrelated adult. gnomAD v4.1 reports 0 homozygotes but does not provide the required normolipidemic, untreated adult phenotype data or establish three qualifying heterozygous adults, so the rule cannot be evaluated.
Variant is identified in ≥3 heterozygous or ≥1 homozygous well-phenotyped, untreated, normolipidemic adults (unrelated).
The VCEP requires BS3 Strong evidence to demonstrate more than 90% of wild-type activity for expression/biosynthesis, LDL binding, and internalization in a whole-LDLR-cycle assay using heterologous cells without endogenous LDLR and a mutant plasmid. BS3 Supporting requires the specified whole-cycle results in true homozygous or heterozygous patient cells, or one of the VCEP-listed benign transcription, RNA, minigene, or validated high-throughput assays. No such benign result is reported for NM_000527.5:c.621C>T. PMID:18400033 instead reports aberrant splicing and a 75-nucleotide in-frame deletion, while PMID:31578082 does not mention or test this variant. Therefore the VCEP BS3 rule cannot be satisfied or calibrated for this variant.
Variant meets Level 1 benign functional study criteria. See Table 3. (1) Study of the whole LDLR cycle (LDLR expression/biosynthesis, LDL binding, and LDL internalization) performed in heterologous cells (with no endogenous LDLR) transfected with mutant plasmid. Assay result of >90% of wild-type activity in expression/biosynthesis, binding AND internalization. Note: studies of only part of the LDLR cycle are not eligible for BS3 or BS3_Supporting.
The VCEP requires lack of segregation in at least two unrelated index-case families, at least two informative meioses in each family, and at least one unaffected relative with LDL-C below the 50th centile who carries the variant. No such unrelated-family non-segregation data or unaffected carrier phenotype is documented.
Lack of segregation in ≥2 index case families (unrelated), when data is available for ≥2 informative meioses in each family. ... Caveat: must be ≥1 unaffected relative (LDL-C <50th centile) who is positive for the variant.
The VCEP applies BP2 at Supporting strength when an FH patient with a heterozygous phenotype has a pathogenic or likely pathogenic variant in LDLR in trans, APOB, or PCSK9, and the candidate is an additional LDLR variant. The available reports describe c.621C>T among heterozygous FH patients and identify homozygous cases, but they do not document an additional pathogenic or likely pathogenic LDLR, APOB, or PCSK9 variant in an FH patient with a heterozygous phenotype, nor do they establish phase. Therefore, BP2 cannot be assessed.
If a FH patient with a heterozygous phenotype has a pathogenic or likely pathogenic variant in LDLR (in trans), APOB or PCSK9, BP2 is applicable to any additional LDLR variants.
The VCEP limits BP4 to REVEL <=0.5 for missense variants or no predicted splice impact using MaxEntScan. This variant is synonymous, so the missense path does not apply. The available computational result is SpliceAI max delta 0.981, which is not the predictor named by the governing rule; PMID:18400033 reports SPLICESITEFINDER-based splice impact rather than MaxEntScan. Therefore the required MaxEntScan no-impact assessment is unavailable, and BP4 cannot be assessed without applying an ungoverned predictor.
REVEL score ≤0.5 (missense variants), or no predicted impact to splicing using MaxEntScan (see Fig. 2 for suggested thresholds).
The variant is synonymous, satisfying the first applicability condition in the VCEP BP7 rule. However, the rule requires that BP7 also meet BP4, and BP4 is not assessed because the required MaxEntScan no-splice-impact result is unavailable. The available SpliceAI max delta 0.981 and the variant-specific SPLICESITEFINDER evidence cannot substitute for the VCEP-named MaxEntScan assessment.
Variant is synonymous. ... Caveat: variant must also meet BP4 (i.e. no predicted impact on splicing).
PS1 is not applicable because the queried variant is synonymous, NP_000518.1:p.(Gly207=), whereas the LDLR VCEP rule is restricted to a missense variant at the same codon that predicts the same amino-acid change. The available splice-impact result does not convert this synonymous variant into a missense variant for purposes of this rule.
Missense variant at the same codon as a variant classified pathogenic (by these guidelines), and predicts the same amino acid change. Caveat: there is no in silico predicted splicing impact for either variant.
PM1 is not applicable because the LDLR VCEP specification limits this criterion to a missense variant located in exon 4 or a missense change affecting one of the specified conserved cysteine residues. Although the variant is in exon 4, c.621C>T is synonymous (p.Gly207=), so it does not meet the rule's required missense variant type. vcep_materials.json contains no LDLR domain_tables entry; no additional domain route is therefore available or needed.
Missense variant located in exon 4, or a missense change in one of 60 highly conserved cysteine residues (listed in Supp. Table 4). Caveat: variant must also meet PM2.
The VCEP PM4 rule is limited to in-frame deletions or insertions smaller than one whole exon, or in-frame whole-exon duplications, provided they are not considered in any PVS1 criteria. The submitted variant is a single-nucleotide synonymous substitution, NM_000527.5:c.621C>T, not an in-frame deletion, insertion, or whole-exon duplication. Although PMID:18400033 demonstrated that the substitution causes aberrant splicing with a secondary 75-bp in-frame deletion, the primary variant type is outside the PM4 applicability named by the VCEP. The rule's PM2 caveat is met by the gnomAD v4.1 grpmax FAF of 6.8e-7, but that does not make PM4 applicable.
In-frame deletion/insertions smaller than one whole exon, or in-frame whole-exon duplications not considered in any PVS1 criteria. Caveat: variant must also meet PM2.
PM5 is not applicable because both VCEP PM5 routes require the queried variant to be missense at the same codon as one or at least two pathogenic missense variants and to predict a different amino-acid change. This variant is synonymous, NP_000518.1:p.(Gly207=), so it cannot satisfy either route.
Missense variant at a codon with ≥2 missense variants classified pathogenic (by these guidelines), and predicts a different amino acid change. ... Missense variant at the same codon as a variant classified pathogenic (by these guidelines), and predicts a different amino acid change.
The ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.2 marks PP2 as not applicable. The VCEP states: "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease." NM_000527.5:c.621C>T in LDLR is a synonymous (silent) substitution predicted to produce NP_000518.1:p.(Gly207=). This determination was made deterministically from the VCEP criteria specification, prior to LLM adjudication.
deterministic_prefilter: vcep_not_applicable
The LDLR FH VCEP marks PP5 as not applicable and states that the criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Therefore, ClinVar or literature pathogenic assertions are not adjudicated as PP5.
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
The ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.2 marks BP1 as not applicable. NM_000527.5:c.621C>T in LDLR is a synonymous (silent) substitution predicted to produce NP_000518.1:p.(Gly207=). This determination was made deterministically from the VCEP criteria specification, prior to LLM adjudication.
deterministic_prefilter: vcep_not_applicable
The ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.2 marks BP3 as not applicable. NM_000527.5:c.621C>T in LDLR is a synonymous (silent) substitution predicted to produce NP_000518.1:p.(Gly207=). This determination was made deterministically from the VCEP criteria specification, prior to LLM adjudication.
deterministic_prefilter: vcep_not_applicable
The LDLR FH VCEP marks BP5 as not applicable for this VCEP. No alternate-molecular-basis evidence is adjudicated under BP5, regardless of any case-level findings.
Variant found in a case with an alternate molecular basis for disease.
The LDLR FH VCEP marks BP6 as not applicable and states that the criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Therefore, benign assertions from reputable sources are not adjudicated as BP6.
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Every interpreted variant in LDLR, mapped onto the exon structure of NM_000527.5. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| Remaining individuals1 / 62,488 | 1.6e-05 |
| European (non-Finnish)3 / 1,179,920 | 2.5e-06 |
This variant is present in gnomAD v4.1 (AF= 2.47891e-06; MAF= 0.00025%, 4/1613612 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.60031e-05; MAF= 0.00160%, 1/62488 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.
Absent from gnomAD v2.1.
Not available in gnomAD-Canada v1.0.
The VCEP limits PP3 to REVEL >=0.75 for missense variants or predicted splice impact using MaxEntScan. This variant is synonymous, so the missense path does not apply. The available computational result is SpliceAI max delta 0.981, and PMID:18400033 reports a splice prediction with SPLICESITEFINDER plus aberrant splicing; neither is MaxEntScan. Because the governing rule names MaxEntScan and no MaxEntScan result or the VCEP's Figure 2 threshold application is available, PP3 cannot be assessed without substituting an ungoverned predictor.
REVEL score ≥0.75 (missense variants), or predicted impact to splicing using MaxEntScan (see Fig. 2 for suggested thresholds).
The VCEP limits BP4 to REVEL <=0.5 for missense variants or no predicted splice impact using MaxEntScan. This variant is synonymous, so the missense path does not apply. The available computational result is SpliceAI max delta 0.981, which is not the predictor named by the governing rule; PMID:18400033 reports SPLICESITEFINDER-based splice impact rather than MaxEntScan. Therefore the required MaxEntScan no-impact assessment is unavailable, and BP4 cannot be assessed without applying an ungoverned predictor.
REVEL score ≤0.5 (missense variants), or no predicted impact to splicing using MaxEntScan (see Fig. 2 for suggested thresholds).
The variant is synonymous, satisfying the first applicability condition in the VCEP BP7 rule. However, the rule requires that BP7 also meet BP4, and BP4 is not assessed because the required MaxEntScan no-splice-impact result is unavailable. The available SpliceAI max delta 0.981 and the variant-specific SPLICESITEFINDER evidence cannot substitute for the VCEP-named MaxEntScan assessment.
Variant is synonymous. ... Caveat: variant must also meet BP4 (i.e. no predicted impact on splicing).
SpliceAI predicts possible splice impact for this variant (max delta score = 0.98).
9 paper records listed. 2 cited in the classification.
One new polymorphism in exon 4 (CT at 621, G186G) is also presented in Table 3.
Location Results, ‘Identification and characterisation of new mutations’; Table 3, exon 4 row for C>T at 621 / G186G
Context DGGE screening of all 18 LDLR exons and the promoter region in 141 apparently unrelated heterozygous FH patients, followed by direct sequencing of abnormal fragments; the Table 3 entry lists Hph+ restriction analysis.
aberrant splicing caused by G186G resulted in an in-frame deletion of 75 nucleotides and a stable mRNA
Location Results, paragraphs 1 and 3; Table 1; Fig. 2a
Context The variant was identified during sequencing of LDLR in 1350 clinically diagnosed familial hypercholesterolemia patients after exclusion of known functional LDLR, APOB, and PCSK9 variants. RNA from peripheral blood was reverse-transcribed, exon 4 cDNA was PCR-amplified, and products were analyzed by agarose-gel electrophoresis.
Mutations identified from the patients were shown to have loss of LDLR activity versus wild-type because of either defective endoplasmic reticulum transport or impaired LDL-cholesterol binding activity.
Highlights; Results, “Functional In vitro Characterization of the Point Mutations and Frameshift LDLR Variants Present in the HoFH Patients”
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The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 2.47891e-06; MAF= 0.00025%, 4/1613612 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.60031e-05; MAF= 0.00160%, 1/62488 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.
Absent from gnomAD v2.1.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (10 clinical laboratories) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 3747)
SpliceAI predicts possible splice impact for this variant (max delta score = 0.98).
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52944419, n = 1 times).
This variant does not lie in a statistically significant hotspot.