Submissions for variant NM_152703.5(SAMD9L):c.1877C>T (p.Ser626Leu)

dbSNP: rs1554341671

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000498009	SCV000590703	uncertain significance	not provided	2019-06-25	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 29146900)
Ambry Genetics	RCV001266100	SCV001444272	uncertain significance	Inborn genetic diseases	2019-11-25	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000498009	SCV001508479	pathogenic	not provided	2022-07-27	criteria provided, single submitter	clinical testing	Experimental studies have shown that this missense change affects SAMD9L function (PMID: 29146900, 35310830). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 626 of the SAMD9L protein (p.Ser626Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with SAMD9L-related conditions (PMID: 29146900, 35310830). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 432926). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV004787806	SCV005402315	pathogenic	Ataxia-pancytopenia syndrome	2024-06-27	criteria provided, single submitter	clinical testing	The SAMD9L c.1877C>T (p.Ser626Leu) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, however, functional studies suggest the variant has a damaging effect on protein function (PMID: 29146900). This variant has been reported in individuals with myelodysplasia and ataxia (PMID: 29146900, 35310830, internal data) and was found to segregate with disease. In summary, this variant meets criteria to be classified as pathogenic.
OMIM	RCV002221547	SCV002498725	pathogenic	Spinocerebellar ataxia 49	2022-07-27	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004535565	SCV004748250	likely pathogenic	SAMD9L-related disorder	2023-12-24	no assertion criteria provided	clinical testing	The SAMD9L c.1877C>T variant is predicted to result in the amino acid substitution p.Ser626Leu. This variant has been reported in two related pediatric patients with Myelodysplastic syndrome (MDS) and with loss of heterozygosity on chromosome 7 in transformed cells (Schwartz et al. 2017. PubMed ID: 29146900). Functional studies in Schwartz et al. suggest that this variant results in a gain of SAMD9L protein function and leading to decreased cell proliferation. This variant has also been reported in a family with multiple individuals with spinocerebellar ataxia, and function study showed that this variant decreased levels of SAMD9L (Corral-Juan et al. 2022. PubMed ID: 35310830). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic.