ClinVar Miner

Submissions for variant NM_000337.5(SGCD):c.451T>G (p.Ser151Ala) (rs121909298)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000725810 SCV000339546 uncertain significance not provided 2016-02-09 criteria provided, single submitter clinical testing
Invitae RCV000548096 SCV000638174 uncertain significance Autosomal recessive limb-girdle muscular dystrophy type 2F 2020-08-06 criteria provided, single submitter clinical testing This sequence change replaces serine with alanine at codon 151 of the SGCD protein (p.Ser151Ala). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and alanine. This variant is present in population databases (rs121909298, ExAC 0.06%). This variant has been reported to segregate in an autosomal dominant manner in a family affected with early onset dilated cardiomyopathy (PMID: 10974018). It has been reported in an individual with limb-girdle muscular dystrophy who had a pathogenic variant in SGCB (PMID: 18285821). In addition, in a different large family with a recessive limb girdle muscular dystrophy potentially caused by a different SGCD variant, this variant was not associated with dilated cardiomyopathy or limb girdle muscular dystrophy (PMID: 19259135). This variant has been observed in an individual with myopathy (Invitae). However, in that individual, a pathogenic allele was also identified in LDB3, which suggests that this c.451T>G variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 8176). Experimental studies have shown that this missense change leads to dilated cardiomyopathy in transgenic mice (PMID: 17164264, 23695275) and causes cardiac dysfunction in fruit fly models (PMID: 16432241, 19771157). Functional experiments in vitro suggest that this variant is improperly trafficked to the cellular membrane (PMID: 22095924). In summary, this variant is a rare missense change with a deleterious effect on protein function that has been observed in affected individuals. However, it is also found in the population at an appreciable frequency and there is conflicting evidence as to whether this variant is sufficient to cause disease in isolation. 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 Praxis fuer Humangenetik 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 2021-05-17 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). Five 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)
OMIM RCV000008654 SCV000028863 pathogenic Dilated cardiomyopathy 1L 2014-01-01 no assertion criteria provided literature only
Laboratory for Molecular Medicine, Partners HealthCare 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

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