Submissions for variant NM_152328.5(ADSS1):c.741del (p.Lys248fs)

dbSNP: rs769542442

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Cirak Lab, University Hospital Cologne	RCV000855488	SCV000996618	pathogenic	Fetal akinesia deformation sequence 1; Arthrogryposis multiplex congenita	2019-06-28	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV002234891	SCV002509989	pathogenic	not provided	2023-04-20	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 692295). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with ADSSL1-related conditions (PMID: 31680123). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Lys291Argfs*23) in the ADSSL1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ADSSL1 are known to be pathogenic (PMID: 26506222).
MGZ Medical Genetics Center	RCV002290480	SCV002580623	likely pathogenic	Myopathy, distal, 5	2022-01-18	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002290480	SCV003761334	likely pathogenic	Myopathy, distal, 5	2023-01-25	criteria provided, single submitter	curation	The heterozygous p.Lys248ArgfsTer23 variant in ADSSL1 was identified by our study, in the compound heterozygous state with a variant of uncertain significance (NM_152328.5:c.296G>A), in one individual with distal myopathy (Broad Institute Rare Genomes Project). The p.Lys248ArgfsTer23 variant in ADSSL1 has been previously reported in one individual with adenylosuccinate synthetase-like 1-related distal myopathy (PMID: 31680123), but has been identified in 0.004% (5/112132) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs769542442). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 692295) and has been interpreted as pathogenic by the Cirak Lab of the University Hospital of Cologne and Invitae and as likely pathogenic by MDZ Medical Genetics Center. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 248 and leads to a premature termination codon 23 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the ADSSL1 gene is an established disease mechanism in autosomal recessive adenylosuccinate synthetase-like 1-related distal myopathy. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive adenylosuccinate synthetase-like 1-related distal myopathy. ACMG/AMP Criteria applied: PVS1, PM2_Supporting (Richards 2015).