Submissions for variant NM_152328.5(ADSS1):c.781G>A (p.Asp261Asn)

gnomAD frequency: 0.00003  dbSNP: rs140614802

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Undiagnosed Diseases Network, NIH	RCV000235016	SCV000837707	pathogenic	Myopathy, distal, 5	2018-01-09	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000235016	SCV000893336	likely pathogenic	Myopathy, distal, 5	2022-01-29	criteria provided, single submitter	clinical testing
GeneDx	RCV001589201	SCV001825457	pathogenic	not provided	2020-03-18	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect with reduced enzymatic activity compared to the wild type in vitro. In addition, D304N mRNAs injected into zebrafish embryos resulted in a defective skeletal muscle phenotype (Park et al., 2016); This variant is associated with the following publications: (PMID: 32646962, 32331917, 30853170, 28268051, 26506222)
3billion, Medical Genetics	RCV000235016	SCV002318713	pathogenic	Myopathy, distal, 5	2022-03-22	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000243025, PMID:26506222). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual(PMID: 26506222) and co-segregated with Myopathy, distal, 5 in multiple affected family members (PMID: 26506222). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PS3_S). A missense variant is a common mechanism associated with Myopathy, distal, 5. The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000340). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000235016	SCV002507011	likely pathogenic	Myopathy, distal, 5	2022-05-04	criteria provided, single submitter	curation	The homozygous p.Asp304Asn variant in ADSS1 was identified by our study in 1 individual with distal myopathy 5. The variant has been reported in 4 Korean individuals with distal myopathy 5 (PMID: 26506222), segregated with disease in 4 affected relatives from 2 families (PMID: 26506222), and has been identified in 0.01% (4/28258) of South Asian, 0.01% (2/17392) of East Asian, and 0.006% (1/15946) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs140614802). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 243025) as pathogenic by NIH Undiagnosed Diseases Network and OMIM, and as likely pathogenic by Fulgent Genetics. Animal models in zebrafish have shown that this variant causes distal myopathy 5 (PMID: 26506222). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The presence of this variant in 1 affected homozygote, in combination with a reported variant of uncertain significance that is confirmed in trans, and in 4 individuals with distal myopathy 5 increases the likelihood that the p.Asp304Asn variant is pathogenic (Variation ID: 243026, PMID: 26506222). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM3, PP1 (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001589201	SCV002509970	pathogenic	not provided	2024-09-30	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 304 of the ADSSL1 protein (p.Asp304Asn). This variant is present in population databases (rs140614802, gnomAD 0.01%). This missense change has been observed in individuals with distal myopathy (PMID: 26506222, 32331917). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 243025). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects ADSSL1 function (PMID: 26506222). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003401191	SCV004105375	pathogenic	ADSS1-related disorder	2023-01-30	criteria provided, single submitter	clinical testing	The ADSS1 c.910G>A variant is predicted to result in the amino acid substitution p.Asp304Asn. This variant was reported in the homozygous and compound heterozygous states in multiple individuals with myopathy (Mroczek et al. 2020. PubMed ID: 32331917; Park et al. 2016. PubMed ID: 26506222). Functional studies showed the the variant led to decreased enzyme activity (Park et al. 2016. PubMed ID: 26506222). This variant is reported in 0.014% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-105207568-G-A). This variant is interpreted as pathogenic.
OMIM	RCV000235016	SCV000292394	pathogenic	Myopathy, distal, 5	2016-07-15	no assertion criteria provided	literature only
GenomeConnect, ClinGen	RCV000235016	SCV003761506	not provided	Myopathy, distal, 5		no assertion provided	phenotyping only	Homozygous variant classified as Pathogenic and reported on 10-19-2017 by Lab or GTR ID 505801. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.