Submissions for variant NM_001145809.2(MYH14):c.4088G>A (p.Arg1363His)

gnomAD frequency: 0.00003  dbSNP: rs727504915

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000156300	SCV000206018	uncertain significance	not specified	2014-01-02	criteria provided, single submitter	clinical testing	The Arg1363His variant in MYH14 has not been previously reported in individuals with hearing loss or in large population studies. Computational analyses (bioche mical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) sugge st that the Arg1363His variant may impact the protein, though this information i s not predictive enough to determine pathogenicity. In summary, additional info rmation is needed to determine the clinical significance of this variant.
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	RCV001375354	SCV001572120	uncertain significance	Hearing impairment	2021-04-12	criteria provided, single submitter	clinical testing	PP3_Supporting, BS2_Strong
Ambry Genetics	RCV003162638	SCV003877552	uncertain significance	Inborn genetic diseases	2023-02-09	criteria provided, single submitter	clinical testing	The c.3965G>A (p.R1322H) alteration is located in exon 29 (coding exon 28) of the MYH14 gene. This alteration results from a G to A substitution at nucleotide position 3965, causing the arginine (R) at amino acid position 1322 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
New York Genome Center	RCV003335137	SCV004046552	uncertain significance	Autosomal dominant nonsyndromic hearing loss 4A; Peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome	2023-04-06	criteria provided, single submitter	clinical testing	The c.4088G>A p.(Arg1363His) variant identified in MYH14 has not previously been reported in the affected individuals in the literature and it has been deposited in ClinVar [ClinVar ID: 179510] as a Variant of Uncertain Significance (2 submissions). The c.4088G>A variant is observed in 23 out of ~582,722 heterozygous alleles (0.0039% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8). The c.4088G>A variant is located in exon 31 of this 43-exon gene and is predicted to replace a moderately conserved arginine amino acid with histidine at position 1363 in the encoded protein. In silico predictions are not in favor of the damaging effect for the p.(Arg1363His) variant [REVEL = 0.388)]; however, there are no functional studiesto support or refute these predictions. A different missense variant p.(Arg1363Cys) affecting the same amino acid residue has been reported in ClinVar [ClinVar ID:1195791] as a Variant of Uncertain Significance (1 submission).Based on available evidence, this c.4088G>A p.(Arg1363His) variant identified in MYH14 is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005089761	SCV005766998	uncertain significance	not provided	2024-12-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1322 of the MYH14 protein (p.Arg1322His). This variant is present in population databases (rs727504915, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with MYH14-related conditions. ClinVar contains an entry for this variant (Variation ID: 179510). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MYH14 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.