Submissions for variant NM_016239.4(MYO15A):c.7207G>T (p.Asp2403Tyr)

dbSNP: rs878853227

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV002288909	SCV002578307	likely pathogenic	not provided	2022-03-29	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Splicing prediction indicates that there is significant damage to the natural splice site, or there is gain of a relevant cryptic site; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25525159, 27375115, 30245029, 19888295, 32747562)
Labcorp Genetics (formerly Invitae), Labcorp	RCV002288909	SCV004298160	pathogenic	not provided	2023-04-28	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 236037). This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 2403 of the MYO15A protein (p.Asp2403Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with deafness (PMID: 19888295, 32747562). It has also been observed to segregate with disease in related individuals. This variant is also known as c.7545G>T (Asp2403fsX2414). 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) performed at Invitae indicates that this missense variant is not expected to disrupt MYO15A protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000225053	SCV005075900	pathogenic	Autosomal recessive nonsyndromic hearing loss 3	2024-04-02	criteria provided, single submitter	clinical testing	Variant summary: MYO15A c.7207G>T (p.Asp2403Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a cryptic exonic 5' splicing donor site in exon 35 that would correspond to an RNA change of r.7206_7218del, translating to p.Asp2403Thrfs*12. However, to our knowledge, these predictions have yet to be confirmed by functional studies. The variant was absent in 249528 control chromosomes. c.7207G>T has been reported in the literature as the most common non-GJB2 hearing-loss mutation in the Palestinian population in homozygous and compound heterozygous genotypes in multiple individuals affected with early onset pre-lingual hearing loss (example, Abu Rayyan_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 32747562). ClinVar contains an entry for this variant (Variation ID: 236037). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000225053	SCV005644765	pathogenic	Autosomal recessive nonsyndromic hearing loss 3	2024-04-02	criteria provided, single submitter	clinical testing
Laboratory of Prof. Karen Avraham, Tel Aviv University	RCV000225053	SCV000281982	pathogenic	Autosomal recessive nonsyndromic hearing loss 3	2016-02-16	no assertion criteria provided	research	Congenital, profound HL
Hereditary Research Laboratory, Bethlehem University	RCV000225053	SCV000538097	pathogenic	Autosomal recessive nonsyndromic hearing loss 3	2016-06-04	no assertion criteria provided	research	Severe to Profound