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.1 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.2 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.3 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.4 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.5
MYH7
Final classification
Likely Benign
MYH7 c.4909G>A · p.Ala1637Thr
MYH7
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.
ClinGen Cardiomyopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MYH7 Version 2.0 v2.0 criteria-combination framework: matched Rule18 (1 Benign.Strong + 1 Benign.Supporting) with applied criteria: BS1 strong benign, BP6 supporting benign; maps to Likely Benign.
Classification rationale
BS1BP6
Likely Benign
MYH7 c.4909G>A
BS1 + BP6
→
Likely Benign
Gene diagram
· NM_000257.4 · variants mapped to exon structure
MYH7
NM_000257.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 15 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
BS1
strong
Benign
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 v2.1 grpmax FAF=0.00062247 (≥0.0001 BS1 threshold)gnomAD v4.1 grpmax FAF=0.00080614 (≥0.0001 BS1 threshold)African/Af Am: v2.1 22/24
Assessed · not applied
Pathogenic
PS1
No other nucleotide change is known to produce the same amino acid change p.(Ala1637Thr) that has been classified as pathogenic.
PS2
No de novo occurrence of NM_000257.4:c.4909G>A has been reported in any reviewed publication or database.
PS3
No functional studies have been performed on p.(Ala1637Thr).
PS4
No case-control study demonstrates enrichment of this variant in affected individuals compared to controls.
PM1
The VCEP defines the PM1 cluster region as codons 167-931 (ENST00000355349 / NM_000257.4).
PM2
gnomAD grpmax FAF (v2.1: 0.00062247; v4.1: 0.00080614) substantially exceeds the VCEP PM2 threshold of ≤0.00004 (upper bound 95% CI).
PM5
No different missense variant at codon 1637 has been classified as pathogenic or likely pathogenic per VCEP-modified guidelines.
PM6
No assumed de novo occurrence of this variant has been reported without confirmation of maternity and paternity.
PP1
No segregation data are available for this variant.
PP3
REVEL score is 0.577, which is below the VCEP-recommended threshold of ≥0.70 for PP3.
Benign
BA1
gnomAD grpmax FAF (v2.1: 0.00062247; v4.1: 0.00080614) is below the VCEP BA1 threshold of ≥0.001.
BS3
No functional studies demonstrating no damaging effect exist for p.(Ala1637Thr).
BS4
No non-segregation data are available for this variant.
BP2
No data are available on co-occurrence of this variant in trans or cis with a pathogenic variant.
BP4
REVEL score is 0.577, which exceeds the VCEP BP4 threshold of ≤0.40.
N/A · 8
PVS1 · PP2 · PP4 · PP5 · BS2 · BP1 · BP5 · BP7
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 7.93021e-05; MAF= 0.00793%, 128/1614080 alleles, homozygotes = 1) and has highest observed frequency in the African/African American population (AF= 0.000987562; MAF= 0.09876%, 74/74932 alleles, homozygotes = 1); grpmax FAF= 0.00080614.
v2.1
This variant is present in gnomAD v2.1 (AF= 8.83986e-05; MAF= 0.00884%, 25/282810 alleles, homozygotes = 1) and has highest observed frequency in the African/African American population (AF= 0.00088141; MAF= 0.08814%, 22/24960 alleles, homozygotes = 1); grpmax FAF= 0.00062247.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.00016291951775822744, 3/18414 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0079%
· 128 / 1,614,080
1 hom · FAF 0.081%
1 hom · FAF 0.081%
African/African American 74 / 74,932 |
0.099% 1 hom |
Middle Eastern 2 / 6,068 |
0.033% |
South Asian 15 / 91,088 |
0.016% |
Remaining individuals 5 / 62,482 |
0.008% |
Admixed American 4 / 60,008 |
0.0067% |
East Asian 2 / 44,898 |
0.0045% |
Ashkenazi Jewish 1 / 29,606 |
0.0034% |
European (non-Finnish) 25 / 1,180,050 |
0.0021% |
+ 2 not observed (European (Finnish), Amish)
gnomAD v2.1
0.0088%
· 25 / 282,810
1 hom · FAF 0.062%
1 hom · FAF 0.062%
African/African American 22 / 24,960 |
0.088% 1 hom |
East Asian 1 / 19,950 |
0.005% |
South Asian 1 / 30,616 |
0.0033% |
Admixed American 1 / 35,440 |
0.0028% |
+ 4 not observed (Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals)
gnomAD Canada 🇨🇦
0.016%
· 3 / 18,414
0 hom · FAF 0.08%
0 hom · FAF 0.08%
African/African American 3 / 1,016 |
0.3% |
+ 8 not observed (Latino/Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, European (non-Finnish), Remaining individuals, South Asian)
ClinVar
This variant has been reported in ClinVar as Likely benign (7 clinical laboratories) and as Uncertain significance (3 clinical laboratories) and as Benign (1 clinical laboratory) and as Uncertain Significance (1 clinical laboratory) and as Likely Benign by ClinGen Cardiomyopathy Variant Curation Expert Panel (expert panel). (ClinVarID = 43044)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.577. BayesDel score = -0.0637112.
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
9Sources
Triaged references · 10 PMIDs not cited in assessment
23782526 ↗
Somatic MYH7, MYBPC3, TPM1, TNNT2 and TNNI3 mutations in sporadic hypertrophic cardiomyopathy.
CLINVAR
24033266 ↗
A systematic approach to assessing the clinical significance of genetic variants.
CLINVAR
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
29300372 ↗
Adaptation and validation of the ACMG/AMP variant classification framework for MYH7-associated inherited cardiomyopathies: recommendations by ClinGen's Inherited Cardiomyopathy Expert Panel.
CLINVAR
20624503 ↗
Prevalence and spectrum of mutations in a cohort of 192 unrelated patients with hypertrophic cardiomyopathy.
CLINVAR
22958901 ↗
Burden of rare sarcomere gene variants in the Framingham and Jackson Heart Study cohorts.
CLINVAR
14607462 ↗
American College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy. A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines.
CLINVAR
23403236 ↗
Roadmap to determine the point mutations involved in cardiomyopathy disorder: a Bayesian approach.
CLINVAR