14-23425316-C-T

Position:

chr14-23425316-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM5PP2PP5_Very_Strong

The NM_000257.4(MYH7):c.2389G>A(p.Ala797Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,614,034 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A797P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:31

Conservation

PhyloP100: -0.114

Variant links:

Genes affected

MYH7 (HGNC:7577): (myosin heavy chain 7) Muscle myosin is a hexameric protein containing 2 heavy chain subunits, 2 alkali light chain subunits, and 2 regulatory light chain subunits. This gene encodes the beta (or slow) heavy chain subunit of cardiac myosin. It is expressed predominantly in normal human ventricle. It is also expressed in skeletal muscle tissues rich in slow-twitch type I muscle fibers. Changes in the relative abundance of this protein and the alpha (or fast) heavy subunit of cardiac myosin correlate with the contractile velocity of cardiac muscle. Its expression is also altered during thyroid hormone depletion and hemodynamic overloading. Mutations in this gene are associated with familial hypertrophic cardiomyopathy, myosin storage myopathy, dilated cardiomyopathy, and Laing distal myopathy. [provided by RefSeq, May 2022]

MYH7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000257.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr14-23425316-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1476852.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant where missense usually causes diseases, MYH7

PP5

Variant 14-23425316-C-T is Pathogenic according to our data. Variant chr14-23425316-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23425316-C-T is described in Lovd as [Pathogenic]. Variant chr14-23425316-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4 linkuse as main transcript	c.2389G>A	p.Ala797Thr	missense_variant	21/40	ENST00000355349.4
MYH7	NM_001407004.1 linkuse as main transcript	c.2389G>A	p.Ala797Thr	missense_variant	20/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.2389G>A	p.Ala797Thr	missense_variant	21/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251468

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000287

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000297

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000310

Hom.:

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:31

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:9

Pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jul 23, 2014	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Ala797Thr (c.2389 G>A) in the MYH7 gene. We classify it as likely disease causing, based on the data reviewed below. The variant has been observed in 14 families with HCM thought to originate from the same founder and an additional 20 presumably unrelated patients with HCM. There is strong segregation data within the founder families and moderate segregation data in other cases. The variant was first published by Moolman-Smook et al in 1995. They reported one Caucasian South African family in which the variant segregated with cardiomyopathy in four first degree relatives. They subsequently identified the variant in several other families and reported that haplotype analysis was consistent with a founder effect (Moolman-Smook et al 2000). This same group published a review that notes that they have observed p.Ala797Thr in 14 families with 80 carriers of this variant (Bink et al 2009). In studying these kindreds the authors have observed that this variant is associated with age-dependent penetrance, with only 2/3 of carriers having hypertrophy by age 35. The variant was also correlated with reduced diastolic dysfunction. This variant has also been observed in patients with HCM outside of South Africa. Van Driest et al (2004) observed the variant in 2 of 389 patients with HCM, ancestry not reported. The variant was reported in a paper from Carolyn Ho's group on echo and MRI phenotyping in sarcomere variant carriers who do not yet have a diagnosis of HCM (Valente et al 2013). Presumably the variant was first identified in a patient with HCM, though that is not explicitly stated in the paper. Kassen et al (2013) observed the variant in 1 of 192 HCM patients in their Egyptian cohort. Nunez et al (2013) observed the variant in 2 of 104 HCM patients in their Spanish cohort. One of the patients also carried p.Arg1022Pro in MYBPC3. Multiple disease associated variants have been reported at either the same or nearby codons (p.Ala797Pro and p. Lue796Phe) (CardioGenomics http://genepath.med.harvard.edu). Conservation analysis indicates that Alanine is partially conserved at this position across species. In silico analysis predicts the variant to be tolerated (SIFT) or benign (polyphen). In total the variant has been seen in ~5/7402 published controls and individuals from publicly available population datasets. The variant was recently reported online in 1 of 2206 African-American individuals and 0 of 4300 Caucasian individuals in the NHLBI Exome Sequencing Project dataset (as of December 19th, 2013). The phenotype of that individual is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in this dataset so this does not necessarily rule out pathogenicity (Pan et al 2012). It is also listed in dbSNP (rs3218716) with the following frequencies in the relevant HapMap samples: 0/60 Caucasians, 1/43 Chinese individuals, 1/86 Japanese individuals, 0/60 African individuals, 1/46 Mexican individuals, 1/88 Italian individuals. The inconsistency between the ESP Caucasian data and the HapMap Caucasian data is curious. We would most likely put more weight on the ESP data. The variant was not observed in the following published control samples: Moolman et al (1995) did not identify the variant in 56 Caucasian and 54 mixed ancestry controls. Van Driest et al (2004) did not observe the variant in 100 African American and 100 Caucasian control samples from Coriell. Nunez et al (2013) did not obs -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 30, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 02, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 7581410, 19287818, 24093860, 28615295, 28420666, 31589614, 33673806, 33297573, 26582918, 30755392, 29260236, 25937619, 26743238, 16858239, 23299917, 25031304, 23233322, 15358028, 10521296, 17125710, 18029407, 25637381, 28166811, 27737317, 26969327, 24793961, 27247418, 27831900, 27532257, 28138913, 28971120, 28606303, 21310275, 28790153, 29687901, 28408708, 25351510, 24111713, 23782526, 23283745, 22857948, 20031618, 19880069, 11186938, 31006259, 32420109, 32233023, 30291343, 31447099, 32894683, 33087929, 35208637, 35653365, 35288587, 34542152, 29300372) -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Mar 07, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Sep 29, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 02, 2023	The MYH7 c.2389G>A; p.Ala797Thr variant (rs3218716; ClinVar Variation ID: 42901), also known as A797T, is a known founder variant in Black South African population (Moolman-Smook 2002). This variant has been shown to co-segregated with disease in multiple individuals and has been identified in multiple unrelated individuals (selected references: Moolman-Smook 2002, Mattos 2016, Walsh 2017). This variant is associated with mild-moderate hypertrophic cardiomyopathy and displays incomplete penetrance (Moolman-Smook 2000). Based on available information, this variant is considered to be pathogenic. References: Mattos BP et al. Prevalence and Phenotypic Expression of Mutations in the MYH7, MYBPC3 and TNNT2 Genes in Families with Hypertrophic Cardiomyopathy in the South of Brazil: A Cross-Sectional Study. Arq Bras Cardiol. 2016 Sep;107(3):257-265. PMID: 27737317. Moolman-Smook J et al. Expression of HCM causing mutations: lessons learnt from genotype-phenotype studies of the South African founder MYH7 A797T mutation. J Med Genet. 2000 Dec;37(12):951-6. PMID: 11186938. Walsh R et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2017 Feb;19(2):192-203. PMID: 27532257. -
Pathogenic, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 08, 2021	PS4, PP1_strong, PM1 -

Hypertrophic cardiomyopathy 1

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 17, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000042901, PMID:7581410, PS1_S). The variant was co-segregated with Cardiomyopathy, hypertrophic, 1 in multiple affected family members with additional meioses meeting strong evidence levels (PMID: 10521296, 17125710, 23233322, 24111713, 19880069, 22857948, 23283745, 16858239, 24093860, 20031618, PP1_S). A different missense change at the same codon has been reported to be associated with MYH7 related disorder (PMID:17125710, PM5_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000024, PM2_M). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 26, 2022	- -

Hypertrophic cardiomyopathy

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 08, 2023	The p.Ala797Thr variant in MYH7 has been identified in >30 individuals with HCM and segregated with disease in >10 affected relatives from several families (Moolman 1995 PMID: 7581410, Moolman-Shook 1999 PMID: 10521296, Moolman-Smook 2000 PMID: 11186938, Van Driest 2004 PMID: 15358028, Laredo 2006 PMID: 17125710, Kassem 2013 PMID: 23233322, Bos 2014 PMID: 24793961, LMM data). This variant has been reported by other clinical laboratories in ClinVar (Variation ID 42901) and has been identified in 0.005% (2/41412) African/African American chromosomes by gnomAD (http://gnomad.broadinstitute.org; v.3.1.2). Please note that for diseases with clinical variability and reduced penetrance, pathogenic variants may be present at a low frequency in the general population. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. Of note, this variant lies in the head region of the protein. Missense variants in this region have been reported and statistically indicated to be more likely to cause disease (Walsh 2017 PMID: 27532257). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM1, PM2_Supporting. -
Pathogenic, criteria provided, single submitter	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Jun 14, 2018	MYH7 Ala797Thr has previously been described in HCM patients from at least 11 centres (Moolman., et al 1995; Van Driest., et al 2004; Laredo., et al 2007; Revera., et al 2008; Kaski., et al 2009; Brito., et al 2012; Marsiglia., et al 2013; Kassem., et al 2013; Berge & Leren., et al 2014; Walsh., et al 2017). Strong co-segregation of this variant with disease has been demonstrated in unrelated families (Moolman., et al 1995; Laredo., et al 2007). The variant is present in the Exome Aggregation Consortium dataset (MAF=0.00003; http://exac.broadinstitute.org/). Moolman et al first identified this variant (1995) and haplotype analysis in subsequent papers led them to suggest it may be a South African founder variant (2000). We have observed the Ala797Thr variant in three unrelated HCM probands, one of these proband also has a second MYH7 variant (p.Arg807His) which was inherited in trans. In a large HCM population study Walsh et al., showed that MYH7 variants identified in HCM cases were found to cluster between amino acids 181- 937 (2017), this implies that variants in this region are likely to cause a HCM phenotype. Based on the adapted ACMG guidelines (Kelly MA, et al., 2018) this variant has been reported in well over 15 HCM probands (PS4), segregates with disease in multiple families (PP1_strong), is located in a known functional domain of MYH7 (PM1) and is rare in the general population (PM2), therefore we classify MYH7 Ala797Thr as "pathogenic". -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 797 of the MYH7 protein (p.Ala797Thr). This variant is present in population databases (rs3218716, gnomAD 0.007%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 10521296, 16858239, 17125710, 19880069, 20031618, 22857948, 23233322, 23283745, 24093860, 24111713). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42901). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYH7 protein function. This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). For these reasons, this variant has been classified as Pathogenic. -

MYH7-related disorder

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	Missense variation is an established mechanism of disease for MYH7-related disorders (PMID: 7731997, 12975413). The c.2389G>A (p.Ala797Thr) variant affects a weakly conserved amino acid and in silico tools used to predict the effect of this variant on protein function yield discordant results. This variant has been previously reported as a heterozygous change in patients with hypertrophic cardiomyopathy (PMID: 27532257, 7581410, 33673806, 11447480, 24793961, 35653365, 17125710, 33297573, 35288587). In addition, this variant has been previously reported as a heterozygous change in onepatient with Wolff-Parkinson-White syndrome (PMID: 32233023). The c.2389G>A (p.Ala797Thr) variant is located in a mutational hotspot for pathogenic variations associated with hypertrophic cardiomyopathy (PMID: 27532257). The c.2389G>A (p.Ala797Thr) variant is presentin the heterozygous state in the gnomAD population database at a frequency of 0.002% (6/251468) and is absent in the homozygous state, thus is presumed to be rare. Based on the available evidence, c.2389G>A (p.Ala797Thr) is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jun 13, 2023	The MYH7 c.2389G>A variant is predicted to result in the amino acid substitution p.Ala797Thr. This variant has been reported in several individuals with autosomal dominant hypertrophic cardiomyopathy (see for example, Bos et al. 2014. PubMed ID: 24793961, Supplemental Table 1; Walsh et al. 2017. PubMed ID: 27532257, Table S1A). It occurs in a region that is enriched for disease-associated missense variants (Human Gene Mutation Database). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-23894525-C-T), and it is classified as likely pathogenic and pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/42901/). We interpret this variant to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	The c.2389G>A;p.(Ala797Thr) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 42901; PMID: 31110529; 23233322; 7581410;18029407;17125710;28606303; 22857948; 28138913; 27831900) - PS4.The variant is located in a mutational hot spot and/or critical and well-established functional domain (IQ) - PM1. The variant is present at low allele frequencies population databases (rs3218716– gnomAD 0.0002629%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The variant co-segregated with disease in multiple affected family members (PMID: 11186938; 17125710) - PP1_strong. In summary, the currently available evidence indicates that the variant is pathogenic. -

Cardiomyopathy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jun 12, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 20, 2023	This missense variant replaces alanine with threonine at codon 797 in the myosin head/motor domain of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in many individuals affected with hypertrophic cardiomyopathy (PMID: 7581410, 10521296, 11186938, 11447480, 15358028, 16858239, 17125710, 20031618, 22857948, 23233322, 23283745, 24093860, 24111713, 24793961, 26969327, 27247418, 27532257, 27737317, 27831900, 28138913, 28615295, 28790153, 33297573, 33673806) and has been shown to segregate with disease in several families (PMID: 11186938, 17125710). This variant is particularly common in the South African individuals affected with hypertrophic cardiomyopathy (PMID: 27841901). This variant has been identified in 6/251468 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Myopathy, myosin storage, autosomal recessive

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 22, 2023

- -

Wolff-Parkinson-White pattern

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Jul 14, 2017

This variant was identified in an individual with Wolff-Parkinson-White syndrome -

Dilated cardiomyopathy 1S

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 17, 2023

- -

Immunodeficiency;C0024312:Lymphopenia;C0085110:Severe combined immunodeficiency disease;C2711630:Combined immunodeficiency;C4023166:Abnormality of T cell physiology;C4023612:Abnormal cellular immune system morphology

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

- -

Myosin storage myopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 22, 2023

- -

MYH7-related skeletal myopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 22, 2023

- -

Congenital myopathy with fiber type disproportion;C1834481:Dilated cardiomyopathy 1S;C1842160:Myosin storage myopathy;C1850709:Myopathy, myosin storage, autosomal recessive;C3495498:Hypertrophic cardiomyopathy 1;C4552004:MYH7-related skeletal myopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 02, 2021

- -

Primary familial dilated cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

- -

Primary familial hypertrophic cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

Low GERP score may suggest that this variant may belong in a lower pathogenicity class -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 30, 2021

The p.A797T pathogenic mutation (also known as c.2389G>A), located in coding exon 19 of the MYH7 gene, results from a G to A substitution at nucleotide position 2389. The alanine at codon 797 is replaced by threonine, an amino acid with similar properties. This mutation has been reported in association with hypertrophic cardiomyopathy (HCM) and has shown a founder effect in the South African population (Moolman JC et al. Hum Mutat. 1995;6(2):197-8; Moolman-Smook JC et al. Am J Hum Genet. 1999;65(5):1308-20; Revera M et al. Cardiovasc Res. 2008;77(4):687-94; Brito D et al. Rev Port Cardiol. 2012;31(9):577-87; Kassem HSh et al. J Cardiovasc Transl Res. 2013;6(1):65-80; Lopes LR et al. Heart. 2015;01(4):294-301; Walsh R et al. Genet. Med. 2017;19(2):192-203). This alteration has also segregated with disease across several families (Moolman-Smook JC et al. Am J Hum Genet. 1999;65(5):1308-20; Moolman-Smook J et al. J Med Genet. 2000;37(12):951-6; Laredo R et al. Rev Esp Cardiol. 2006;59(10):1008-18). Based on the supporting evidence, p.A797T is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

CardioboostCm

Uncertain

0.85

BayesDel_addAF

Uncertain

0.057

BayesDel_noAF

Uncertain

0.030

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.35

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.74

M_CAP

Pathogenic

0.87

MetaRNN

Uncertain

0.71

MetaSVM

Uncertain

-0.16

MutationAssessor

Benign

1.9

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.36

REVEL

Uncertain

0.59

Sift

Benign

0.031

Sift4G

Benign

0.20

Polyphen

0.057

Vest4

0.70

MVP

0.84

MPC

0.95

ClinPred

0.041

GERP RS

0.75

Varity_R

0.17

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over