rs376780156
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
This summary comes from the ClinGen Evidence Repository: The NM_000337.6: c.191T>C variant in SGCD is a missense variant predicted to cause substitution of isoleucine by threonine at amino acid 64 (p.Ile64Thr). The highest minor allele frequency of this variant is 0.0001293 in the Admixed American population of gnomAD v2.1.1 (4/30926 exome chromosomes), which is greater than the LGMD VCEP threshold (0.00009) for PM2_Supporting (criterion not met). The computational predictor REVEL gives a score of 0.63 (PP3, BP4 not met). In summary, there is currently insufficient evidence to determine whether this variant is pathogenic or benign and it is classified as a variant of uncertain significance for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP(LGMD VCEP specifications version 1.0.0; 01/08/2025): no codes applied. LINK:https://erepo.genome.network/evrepo/ui/classification/CA308788/MONDO:0015152/186
Frequency
Consequence
NM_000337.6 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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SGCD | ENST00000337851.9 | c.191T>C | p.Ile64Thr | missense_variant, splice_region_variant | Exon 3 of 9 | 1 | NM_000337.6 | ENSP00000338343.4 | ||
SGCD | ENST00000435422.7 | c.188T>C | p.Ile63Thr | missense_variant, splice_region_variant | Exon 2 of 8 | 1 | ENSP00000403003.2 | |||
SGCD | ENST00000517913.5 | c.191T>C | p.Ile64Thr | missense_variant, splice_region_variant | Exon 5 of 10 | 5 | ENSP00000429378.1 | |||
SGCD | ENST00000524347.2 | n.191T>C | splice_region_variant, non_coding_transcript_exon_variant | Exon 3 of 6 | 5 | ENSP00000430794.1 |
Frequencies
GnomAD3 genomes AF: 0.0000986 AC: 15AN: 152176Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000767 AC: 18AN: 234638Hom.: 0 AF XY: 0.0000626 AC XY: 8AN XY: 127726
GnomAD4 exome AF: 0.0000519 AC: 75AN: 1446290Hom.: 0 Cov.: 31 AF XY: 0.0000529 AC XY: 38AN XY: 718992
GnomAD4 genome AF: 0.0000986 AC: 15AN: 152176Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74342
ClinVar
Submissions by phenotype
not provided Uncertain:4
In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
The SGCD c.191T>C; p.Ile64Thr variant (rs376780156), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 202088). This variant is found in the general population with an overall allele frequency of 0.007% (19/266,042 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.63). However, given the lack of clinical and functional data, the significance of this variant is uncertain at this time. -
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Autosomal recessive limb-girdle muscular dystrophy type 2F Uncertain:2
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 64 of the SGCD protein (p.Ile64Thr). This variant is present in population databases (rs376780156, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with SGCD-related conditions. ClinVar contains an entry for this variant (Variation ID: 202088). 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"). 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. -
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Autosomal recessive limb-girdle muscular dystrophy Uncertain:1
The NM_000337.6: c.191T>C variant in SGCD is a missense variant predicted to cause substitution of isoleucine by threonine at amino acid 64 (p.Ile64Thr). The highest minor allele frequency of this variant is 0.0001293 in the Admixed American population of gnomAD v2.1.1 (4/30926 exome chromosomes), which is greater than the LGMD VCEP threshold (0.00009) for PM2_Supporting (criterion not met). The computational predictor REVEL gives a score of 0.63 (PP3, BP4 not met). In summary, there is currently insufficient evidence to determine whether this variant is pathogenic or benign and it is classified as a variant of uncertain significance for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP(LGMD VCEP specifications version 1.0.0; 01/08/2025): no codes applied. -
Inborn genetic diseases Uncertain:1
The p.I64T variant (also known as c.191T>C), located in coding exon 2 of the SGCD gene, results from a T to C substitution at nucleotide position 191. The isoleucine at codon 64 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Autosomal recessive limb-girdle muscular dystrophy type 2F;C1847667:Dilated cardiomyopathy 1L Uncertain:1
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Dilated cardiomyopathy 1L Uncertain:1
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not specified Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at