Submissions for variant NM_000441.2(SLC26A4):c.3G>C (p.Met1Ile)

gnomAD frequency: 0.00001  dbSNP: rs786204426

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169018	SCV000220162	likely pathogenic	Pendred syndrome	2014-03-16	criteria provided, single submitter	literature only
GeneDx	RCV000579019	SCV000680757	pathogenic	not provided	2019-07-17	criteria provided, single submitter	clinical testing	Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 17876604)
Genome-Nilou Lab	RCV000169018	SCV002027617	likely pathogenic	Pendred syndrome	2021-09-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000579019	SCV002234498	pathogenic	not provided	2024-12-15	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the SLC26A4 mRNA. The next in-frame methionine is located at codon 21. This variant is present in population databases (rs786204426, gnomAD 0.007%). Disruption of the initiator codon has been observed in individuals with SLC26A4-related conditions (PMID: 17876604, 19204907, 21961810, 27997596). ClinVar contains an entry for this variant (Variation ID: 188721). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169018	SCV003844444	likely pathogenic	Pendred syndrome	2023-02-08	criteria provided, single submitter	clinical testing	Variant summary: SLC26A4 c.3G>C (p.Met1Ile) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Two of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 31384 control chromosomes (gnomAD). c.3G>C has been reported in the literature in two compound heterozygous individuals (siblings) affected with Pendred Syndrome in one family (Banghova_2007). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite this variant as pathogenic (n=2) and likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000169018	SCV004041806	pathogenic	Pendred syndrome	2023-10-09	no assertion criteria provided	clinical testing