Variant classification summary

NM_000257.4:c.4909G>A

MYH7 · NP_000248.2:p.(Ala1637Thr) · NM_000257.4

GRCh37: chr14:23885257 C>T · GRCh38: chr14:23416048 C>T

Gene: MYH7 Transcript: NM_000257.4

Final call

Likely Benign

BS1 strong benign BP6 supporting benign

Variant details

Gene

MYH7

Transcript

NM_000257.4

Protein

NP_000248.2:p.(Ala1637Thr)

gnomAD AF

7.930214115781126e-05 (v4.1)

ClinVar

Likely Benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000257.4:c.4909G>A (p.Ala1637Thr) in MYH7 meets BS1 at strong_benign strength: gnomAD grpmax FAF (v2.1: 0.00062247; v4.1: 0.00080614) exceeds the VCEP threshold of ≥0.0001 for MYH7, with highest frequency in the African/African American population (v4.1: 0.099%) and one homozygote observed in each gnomAD dataset.

2

No pathogenic criteria are met. PM1 is not applicable (codon 1637 is outside the VCEP-defined cluster region of codons 167-931). PM2 is not met (gnomAD frequency far exceeds the ≤0.00004 threshold). PP3 is not met (REVEL 0.577 < 0.70 threshold). PS3/PS4/PM5/PM6/PP1/PS1/PS2 all lack supporting evidence.

3

Per VCEP BS1 specifications, 'Criterion BS1 may only be used as standalone evidence to classify a variant as Likely Benign in the absence of conflicting data.' No conflicting pathogenic evidence exists. All pathogenic criteria are either not met or not applicable. This variant is classified as Likely Benign.

4

This assessment is concordant with the ClinGen Cardiomyopathy Expert Panel classification of Likely Benign (ClinVar VariationID: 43044, review status: reviewed by expert panel), with 7 of 12 clinical laboratories also reporting Likely Benign or Benign.

5

One HCM case harboring this variant was reported by Nuñez et al. 2013 (PMID:23782526), in which all five in silico tools predicted A1637T as neutral. The variant was observed alongside established pathogenic mutations in the same cohort but was not functionally characterized.

Final determination: Rule18 in the ClinGen Cardiomyopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MYH7 Version 2.0 v2.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Likely Benign.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	PVS1 is not applicable for MYH7 per the ClinGen Cardiomyopathy VCEP v2.0 specifications. MYH7 missense variants are the predominant disease mechanism; null variants are also reported. This variant is a missense substitution (c.4909G>A, p.Ala1637Thr) and does not fall into PVS1 null-variant buckets.	cspec
PS1	Not met	No other nucleotide change is known to produce the same amino acid change p.(Ala1637Thr) that has been classified as pathogenic. PS1 requires an established pathogenic variant at the same amino acid position.
PS2	Not met	No de novo occurrence of NM_000257.4:c.4909G>A has been reported in any reviewed publication or database. The VCEP requires confirmation of both maternity and paternity for PS2 application.
PS3	Not met	No functional studies have been performed on p.(Ala1637Thr). Nuñez et al. 2013 (PMID:23782526) identified this variant in 1 of 104 HCM patients and all five in silico tools (SIFT, Pmut, PolyPhen, SNAP, PhDSNP) predicted the variant as neutral, but in silico predictions do not constitute functional evidence per VCEP PS3 specifications. No in vitro splicing assay, in vivo knock-in model, or biochemical assay data exist for this variant.	PMID:23782526
PS4	Not met	No case-control study demonstrates enrichment of this variant in affected individuals compared to controls. One HCM case was observed in Nuñez et al. 2013 (1/104 probands), but the variant is present in gnomAD at a frequency inconsistent with a rare dominant disorder (v2.1: 25/282,810 alleles, v4.1: 128/1,614,080 alleles), including one homozygote in each dataset. Formal case-control analysis has not been performed.	gnomad_v2 gnomad_v4 PMID:23782526
PS5	N/A	No reputable source has reported this variant as pathogenic. ClinVar classification is Likely Benign, reviewed by the ClinGen Cardiomyopathy Expert Panel. PS5 requires a reputable source to have recently reported the variant as pathogenic without available evidence for independent evaluation.	clinvar
PM1	Not met	The VCEP defines the PM1 cluster region as codons 167-931 (ENST00000355349 / NM_000257.4). This variant is at codon 1637, which lies outside this region in the light meromyosin (LMN) domain. No pathogenic variant enrichment has been demonstrated for codon 1637.	cspec
PM2	Not met	gnomAD grpmax FAF (v2.1: 0.00062247; v4.1: 0.00080614) substantially exceeds the VCEP PM2 threshold of ≤0.00004 (upper bound 95% CI). The variant is present at highest frequency in the African/African American population (v2.1 AF=0.088%, 22/24,960 alleles; v4.1 AF=0.099%, 74/74,932 alleles) with one homozygote observed in each dataset.	gnomad_v2 gnomad_v4 cspec
PM5	Not met	No different missense variant at codon 1637 has been classified as pathogenic or likely pathogenic per VCEP-modified guidelines. The pm5_candidates search returned no comparator variants at this residue.
PM6	Not met	No assumed de novo occurrence of this variant has been reported without confirmation of maternity and paternity. The VCEP requires phenotype consistent with the gene but SVI guidance on the number of cases needed.
PP1	Not met	No segregation data are available for this variant. The VCEP requires ≥3 segregations (LOD score ≥0.9) for supporting, ≥5 for moderate, and ≥7 for strong evidence.
PP2	N/A	The ClinGen Cardiomyopathy VCEP specifies PP2 is not applicable. Regional enrichment data for MYH7 missense variants is captured by PM1 specifications (Walsh et al. 2019, PMID:30696458).	cspec
PP3	Not met	REVEL score is 0.577, which is below the VCEP-recommended threshold of ≥0.70 for PP3. SpliceAI delta score is 0.00, indicating no predicted splice impact. BayesDel score is −0.0637 (benign range). In silico meta-predictors do not support a pathogenic interpretation.	revel bayesdel spliceai cspec
PP4	N/A	The ClinGen Cardiomyopathy VCEP specifies PP4 as not applicable due to high locus heterogeneity and non-genetic etiologies in inherited cardiomyopathies.	cspec
PP5	N/A	The ClinGen Cardiomyopathy VCEP explicitly designates PP5 as 'Not Applicable for this VCEP' per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. This criterion is not for use in the MYH7 cardiomyopathy framework.	cspec
BA1	Not met	gnomAD grpmax FAF (v2.1: 0.00062247; v4.1: 0.00080614) is below the VCEP BA1 threshold of ≥0.001. The variant does not exceed the stand-alone benign allele frequency cutoff.	gnomad_v2 gnomad_v4 cspec
BS1	Met	gnomAD grpmax FAF (v2.1: 0.00062247; v4.1: 0.00080614) exceeds the VCEP BS1 threshold of ≥0.0001 for MYH7. The variant is present at highest frequency in the African/African American population (v2.1: 22/24,960 alleles, 0.088%; v4.1: 74/74,932 alleles, 0.099%) with one homozygote in each dataset. Per VCEP specifications, BS1 may be used as standalone evidence to classify a variant as Likely Benign in the absence of conflicting data.	gnomad_v2 gnomad_v4 cspec
BS2	N/A	The ClinGen Cardiomyopathy VCEP specifies BS2 as not applicable because inherited cardiomyopathies generally display reduced penetrance, variable expressivity, and adult-onset. Observation in a healthy adult does not rule out pathogenicity.	cspec
BS3	Not met	No functional studies demonstrating no damaging effect exist for p.(Ala1637Thr). While Nuñez et al. 2013 predicted the variant as neutral by all five in silico tools, in silico predictions do not constitute functional evidence per VCEP BS3 specifications (which mirror PS3 specifications).	PMID:23782526
BS4	Not met	No non-segregation data are available for this variant. The VCEP requires ≥2 non-segregations that are highly unlikely to be phenocopies or due to alternate variants.
BP1	N/A	The ClinGen Cardiomyopathy VCEP specifies BP1 as not applicable because pathogenic missense variants have been reported in MYH7 alongside null variants. A missense variant in a gene where missense variants are a known disease mechanism does not qualify for BP1.	cspec
BP2	Not met	No data are available on co-occurrence of this variant in trans or cis with a pathogenic variant. BP2 requires observation in trans with a pathogenic variant in ≥2 cases without more severe phenotype, or in cis with a pathogenic variant.
BP4	Not met	REVEL score is 0.577, which exceeds the VCEP BP4 threshold of ≤0.40. BayesDel score is −0.0637, indicating a slight benign prediction, but the VCEP-recommended REVEL meta-predictor does not support a benign interpretation. SpliceAI delta score is 0.00, consistent with no splice impact.	revel bayesdel spliceai cspec
BP5	N/A	The ClinGen Cardiomyopathy VCEP specifies BP5 as not applicable. Co-occurrence with an established pathogenic or likely pathogenic variant for a non-cardiomyopathy related disease does not reduce the likelihood that a variant is independently disease-causing for cardiomyopathy.	cspec
BP6	Met	Expert panel ClinGen Cardiomyopathy Variant Curation Expert Panel classified as Likely benign.	cspec clinvar
BP7	N/A	BP7 applies to synonymous variants and intronic variants outside the splice consensus sequence. This variant is a missense substitution (c.4909G>A, p.Ala1637Thr) and does not qualify for BP7. SpliceAI predicts no splice impact (delta=0.00), but BP7 is structurally not applicable to missense variants.	spliceai cspec

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