Submissions for variant NM_000337.6(SGCD):c.451T>G (p.Ser151Ala)

gnomAD frequency: 0.00012  dbSNP: rs121909298

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000725810	SCV000339546	uncertain significance	not provided	2016-02-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000548096	SCV000638174	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2F	2022-10-05	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 151 of the SGCD protein (p.Ser151Ala). This variant is present in population databases (rs121909298, gnomAD 0.06%). This missense change has been observed in individual(s) with early onset dilated cardiomyopathy and/or SGCD-related conditions (PMID: 10974018, 19259135). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8176). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SGCD protein function. Experimental studies have shown that this missense change affects SGCD function (PMID: 16432241, 17164264, 19771157, 22095924, 23695275). 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000041407	SCV000740670	uncertain significance	not specified	2017-04-04	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000008654	SCV000883104	uncertain significance	Dilated cardiomyopathy 1L	2018-11-21	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000725810	SCV001247866	uncertain significance	not provided	2020-01-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000041407	SCV001623286	uncertain significance	not specified	2022-02-17	criteria provided, single submitter	clinical testing	Variant summary: SGCD c.451T>G (p.Ser151Ala) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 248134 control chromosomes. The observed variant frequency is approximately 13 fold of the estimated maximal expected allele frequency for a pathogenic variant in SGCD causing Dilated Cardiomyopathy phenotype (1.6e-05), suggesting that the variant may not be pathogenic. c.451T>G has been reported in the literature in families affected with dilated cardiomyopathy (Tsubata_2000, Pugh_2014), limb girdle muscular dystrophies (Trabelsi_2008, Bauer_2009) or Sudden Arrhythmic Death Syndrome (Nunn_2016). However, conflicting co-segregation evidence were found in two studies (Tsubata_2000, Bauer_2009). Therefore, these reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy or other cardiovascular conditions. Transgenic Drosophila with p.S151A had marked impairment of systolic function and significantly enlarged cardiac chambers (Wolf_2006). Transgenic mice with p.S151A developed dilated cardiomyopathy or mild cardiomyopathy (Heydemann_2007, Rutschow_2014). Other functional studies have shown the variant leads to defective intracellular trafficking of the protein (Soheili_2011). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS.
GeneDx	RCV000725810	SCV001793957	uncertain significance	not provided	2021-05-13	criteria provided, single submitter	clinical testing	Reported in association with both DCM and segregated with disease in three individuals from one family (Tsubata et al., 2000) and reported in a patient with LGMD who also harbored a partial duplication of exon 1 in the SGCB gene (Trabelsi et al., 2008); Functional studies demonstrate that this variant may result in improper trafficking to the cellular membrane (Soheili et al., 2012); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 8176; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30564623, 28401079, 19771157, 14564412, 10974018, 16432241, 23695275, 19259135, 18285821, 17164264, 22095924, 31019283)
Fulgent Genetics, Fulgent Genetics	RCV002490339	SCV002788234	uncertain significance	Dilated cardiomyopathy 1L; Autosomal recessive limb-girdle muscular dystrophy type 2F	2022-05-17	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000725810	SCV003819898	uncertain significance	not provided	2023-06-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000548096	SCV003931847	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2F	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000008654	SCV003931848	uncertain significance	Dilated cardiomyopathy 1L	2023-02-08	criteria provided, single submitter	clinical testing
OMIM	RCV000008654	SCV000028863	pathogenic	Dilated cardiomyopathy 1L	2014-01-01	no assertion criteria provided	literature only
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041407	SCV000065102	uncertain significance	not specified	2009-11-03	no assertion criteria provided	clinical testing
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000008654	SCV000238412	uncertain significance	Dilated cardiomyopathy 1L	2014-07-17	no assertion criteria provided	research	This test identified a missense variant (c.451T>G; p.Ser151Ala) in the SGCD gene, which is associated with dilated cardiomyopathy 1L (autosomal dominant) and limb girdle muscular dystrophy type 2F (autosomal recessive). This variant was found in two families tested for dilated cardiomyopathy and limb girdle muscular dyatrophy (Tsubata et al. 2000, PMID: 10974018; Trabelsi et al. 2008, PMID: 18285821). Functional analysis suggests that this variant may be associated with dilated cardiomyopathy (Heydemann et al. 2007, PMID: 17164264) or "a mild, subclinical phenotype of cardiomyopathy" (Rutschow et al. 2014, PMID: 23695275), but a previous report found this variant to be present in individuals unaffected with dilated cardiomyopathy (Bauer et al. 2009, PMID: 19259135). Due to lack of clear association of the gene and variant with dilated cardiomyopathy, c.451T>C; p.Ser151Ala is considered a variant of unknown significance. This variant was inherited from the affected mother with Long QT syndome and also observed in the proband’s older brother. This variant was not observed in the younger brother and maternal grandmother. In this family, the variant did not segregate with disease, making it less likely to be associated with the cardiac findings.
OMIM	RCV000681610	SCV000809050	pathogenic	MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 6, DIGENIC	2014-01-01	no assertion criteria provided	literature only