Submissions for variant NM_004393.6(DAG1):c.2123C>T (p.Thr708Met)

gnomAD frequency: 0.00004  dbSNP: rs758254304

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000733878	SCV000861981	uncertain significance	not provided	2018-06-25	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000818915	SCV000959553	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2P; Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A9	2021-08-27	criteria provided, single submitter	clinical testing	This sequence change replaces threonine with methionine at codon 708 of the DAG1 protein (p.Thr708Met). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs758254304, ExAC 0.008%). This variant has not been reported in the literature in individuals affected with DAG1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
GeneDx	RCV000733878	SCV002574668	uncertain significance	not provided	2022-09-09	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Athena Diagnostics	RCV000733878	SCV002770797	uncertain significance	not provided	2022-08-05	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000733878	SCV003830436	uncertain significance	not provided	2019-03-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003303222	SCV004002296	likely benign	Inborn genetic diseases	2023-04-26	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.